Risperidone Approved to Treat Schizophrenia in Children

The U.S. Food and Drug Administration (FDA) has approved the use of risperidone (Risperdal) in children and adolescents to treat schizophrenia and mania or mixed episodes of bipolar I disorder, making it the first atypical antipsychotic drug approved for either disorder in young patients.

The FDA announced last month that risperidone is approved for the treatment of schizophrenia in adolescents aged 13 to 17 and for the short-term treatment of manic or mixed episodes of bipolar I disorder in children and adolescents aged 10 to 17. Risperidone was approved in October 2006 for treating irritability associated with autistic disorders in children and adolescents aged 5 to 16 years.

The approval is based on clinical studies conducted by the manufacturer, Janssen, a Johnson & Johnson subsidiary, at the request of the FDA under the federal Best Pharmaceuticals for Children Act (BCPA). Previously, the FDA had not approved an antipsychotic drug for treatment of schizophrenia in younger patients, and only lithium had been approved for the treatment of bipolar disorder in children as young as 12. The BCPA provides an incentive for drug companies that are directly asked by the FDA to conduct much-needed drug trials in children by extending drug patents or exclusivity period for six months.

This approval is notable because antipsychotic drugs have been prescribed in an off-label manner for children and adolescents for many years, with little evidence-based guidance. Randomized, blinded, controlled studies of these drugs in pediatric populations have been rare. Practitioners have to rely primarily on the drugs' known effects in adult patients and anecdotal information in children while using a trial-and-error approach.

Two studies lasting six and eight weeks were conducted on a total of 417 patients aged 13 to 17 with schizophrenia. Risperidone at a dosage ranging from 0.15 mg/day to 6 mg/day resulted in significantly greater reduction in total Positive and Negative Syndrome Scale (PPANSS) scores than did placebo. Most notably, dosage higher than 3 mg/day did not lead to better efficacy, but increased the number of adverse events.

A third study, this one lasting three weeks, was conducted in 169 children with bipolar I disorder aged 10 to 17 who were experiencing a manic or mixed episode. The two dose groups treated with risperidone had a significantly greater reduction in Young Mania Rating Scale (YMRS) scores than the placebo group. The dose group who received 3 to 6 mg/day of risperidone did no better than the group who received 0.5 to 2.5 mg/day.

APA Says FDA's Action Important

“Schizophrenia and bipolar disorders are severely disabling to patients and devastating to their families,” said APA President Carolyn Robinowitz, M.D., in a press release in response to the FDA approval.“ For many children with these disorders, the FDA's action today provides additional information to guide treatment options in these special populations. We anticipate that the approval of this medication will encourage federal research agencies to accelerate urgently needed studies of mental disorders in children.”

The off-label use of psychoactive drugs in younger patients and the lack of adequate clinical evidence in this population have been sources of controversy. The varying degrees of suicide risk associated with antidepressant use among pediatric and adolescent populations and adult age groups is an example of the complex effects that require more clinical studies. Misconceptions about mental illness have exacerbated public confusion over medications to treat these disorders.

Controversy Over Adverse Events

In recent years, atypical antipsychotics have been the subject of emerging safety concerns, especially regarding glucose metabolism and significant weight gain, which led the FDA to mandate a label warning for all atypical antipsychotics (Psychiatric News, October 17, 2003).

These adverse effects in adult patients were similarly observed in pediatric studies. Weight gain linked to risperidone was reported in 14 percent of 103 patients who participated in the long-term, open-label extension of one of the schizophrenia studies assessed by the FDA. The average weight increase was 9.0 kg (19.8 lb) after eight months. In the three-week clinical trial of children with bipolar I disorder, a significantly higher weight gain was seen in the risperidone group than in the placebo group.

Another notable adverse effect seen in pediatric as well as adult patients taking atypical antipsychotics is elevated prolactin levels, which were as frequent as 87 percent in these pediatric trials. Milk production and enlarged breasts have also been reported.

The recommended risperidone dosage for adolescents with schizophrenia is initially 0.5 mg daily, titrated upward by 0.5 to 1 mg daily depending on tolerability, up to a maximum of 3 mg daily. For the treatment of bipolar mania in pediatric patients, risperidone should be initiated at 0.5 mg once daily and titrated upward by 0.5 to 1 mg daily as tolerated, to a target dose of 2.5 mg daily.

Thomas Laughren, M.D., director of the FDA's Division of Psychiatry Products, and Dianne Murphy, M.D., director of its office of Pediatric Therapeutics, both emphasized at the press conference that the dose and response data obtained from these studies provide important insight for practitioners when they treat younger patients. A key finding “is that there didn't seem to be any higher efficacy from the higher doses compared to the lower doses,” said Laughren. “We see this as a major benefit coming out of the pediatric program, which is a better understanding of dose response.”

Laughren acknowledged that the agency's requests for pediatric studies had been issued for other antipsychotics and that studies of those drugs are underway or under review.

The updated prescribing information for risperidone is posted at<www.risperdal.com/risperdal/shared/pi/risperdal.pdf>.▪